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Trial after trial has demonstrated greater efficacy of high-dose over usual-dose statin therapy in reducing levels of atherogenic lipoproteins and cardiovascular disease (CVD) risk. But as Boekholdt et al. dicsuss in a recent JACC article, the "how" is a little tricky. Given the tremendous levels of inter-individual variability of reductions in low-density lipoprotein cholesterol (LDL-C), non–high-density lipoprotein cholesterol (HDL-C), or apolipoprotein B levels achieved with statin therapy, questions about who reaches targets on high-dose statins and whether patients hitting very low lipid levels lower their CVD risk have come to the forefront.

To help find some answers to these questions, Boekholdt et al. conducted a meta-analysis of individual patient data from eight randomized controlled statin trials involving 38,153 patients allocated to statin therapy. A total of 6,286 major cardiovascular events occurred in 5,387 study participants during 155,573 person-years of follow-up.

Among the 18,677 patients assigned to high-dose statin therapy (either atorvastatin 80 mg or rosuvastatin 20 mg), the mean achieved LDL-C level was 69.6 mg/dl. Notably, more than 40% of these patients did not reach an LDL-C target <70 mg/dl, a substantial missed opportunity.

There were no real surprises when it came to risk estimates for cardiovascular events by categories of achieved LDL-C: lower was definitely better. Patients achieving an LDL-C <50 mg/dl cut their risk of major coronary events by more than half, compared to those with an LDL-C level >175 mg/dl (hazard ratio = 0.47; 95% confidence interval 0.36-0.61) and the actual event rate was one-tenth that of their more LDL-C-burdened peers. "Similar findings were found when the data were analyzed for apoliporotein B and for non-HDL cholesterol," the authors added, "two measurements that may be better than LDL-C as risk predictors, but which are not as familiar to the general public."

Moreover, as the investigators’ analysis shows, some patients achieve a very large reduction of atherogenic lipoprotein levels, whereas others respond very poorly—highlighting the disparities in the current management of dyslipidemia.

These differences are reflected in the various guidelines for lipid management: the old US ATP III guidelines recommended an LDL-C goal of <100 mg/dl for patients with coronary heart disease risk factors; European guidelines focus on a goal of ~100 mg/dl for people at high CVD risk; and recently, the ACC/AHA guideline update abandoned LDL-C targets and dose-titration, stating that measurement of on-treatment LDL-C should only be used for the purpose of assessing adherence. In its place, the guideline update recommends either moderate- or high-intensity statin therapy (based on underlying risk categories).

In an editorial accompanying the meta-analysis, Anthony DeMaria, MD, and Ori Ben-Yehuda, MD, detail the "lower is better" mantra that has led to "an inexorable march to lower LDL-C goals, particularly for secondary prevention." While noting that the results of the current meta-analysis support this trend, Drs. DeMaria and Yehuda also found some limitations—most importantly, the larger statin trials included in this analysis examined fixed doses of statins, rather than those that relied on a strategy of individualized goal attainment. "Hence, it remains unclear whether it is the LDL-C level achieved or the patient’s ability to respond to a statin dose that is the key determinant of the better outcomes."

As Dr. Boekholdt and colleagues stated, there are many factors affecting LDL-C reduction and achieved levels, including presence of diabetes, gender, genetics, and—chief among these—patient adherence. Given this multifactorial impact on LDL-C level and cardiovascular risk, Drs. DeMaria and Yehuda conclude, "The present meta-analysis does not disprove the 2013 ACC/AHA guideline’s contention that there are inadequate data at the present time to indicate specific LDL-C targets of therapy... It is indeed regrettable that more than 25 years after the first ATP guidelines, we still do not have clear-cut evidence on what the appropriate LDL-C targets of therapy should be. The findings from the present meta-analysis will hopefully further spur the design and implementation of lipid trials assessing specific LDL-C targets, rather than specific drug doses."

"Even in the optimal setting of a randomized controlled trial, more than 40% of patients assigned to high-dose statin therapy do not reach an LDL-C level <70 mg/dl," Dr. Boekholdt and colleagues noted, leading them to examine other lipid-lowering options. Data from trials with PCSK9 inhibitors suggest that the large majority of patients treated with those agents may be able to reach LDL-C levels <70 mg/dl.